The n e w e ng l a n d j o u r na l of m e dic i n e

in patients with atrial fibrillation: a meta-analysis of random­ 10. Romiti GF, Pastori D, Rivera-Caravaca JM, et al. Adherence
ised trials. Lancet 2014;​383:​955-62.
5. Kistler JP, Singer DE, Millenson MM, et al. Effect of low-
intensity warfarin anticoagulation on level of activity of the
hemostatic system in patients with atrial fibrillation. Stroke
1993;​24:​1360-5.
6. Lip GYH, Keshishian A, Li X, et al. Effectiveness and safety
of oral anticoagulants among nonvalvular atrial fibrillation pa-
tients. Stroke 2018;​49:​2933-44.
7. Chao TF, Chan Y-H, Chiang C-E, et al. Early rhythm control
and the risks of ischemic stroke, heart failure, mortality, and
adverse events when performed early (<3 months): a nationwide
cohort study of newly diagnosed patients with atrial fibrillation.
Thromb Haemost 2022 March 23 (Epub ahead of print).
8. Kim D, Yang P-S, You SC, et al. Age and outcomes of early
rhythm control in patients with atrial fibrillation: nationwide
cohort study. JACC Clin Electrophysiol 2022;​8:​619-32.
9. Lip GYH. The ABC pathway: an integrated approach to im-
prove AF management. Nat Rev Cardiol 2017;​14:​627-8.
to the ‘atrial fibrillation better care’ pathway in patients with
atrial fibrillation: impact on clinical outcomes-a systematic re-
view and meta-analysis of 285,000 patients. Thromb Haemost
2022;​122:​406-14.
11. Chao T-F, Joung B, Takahashi Y, et al. 2021 focused update
consensus guidelines of the Asia Pacific Heart Rhythm Society
on Stroke Prevention In Atrial Fibrillation: executive summary.
Thromb Haemost 2022;​122:​20-47.
12. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guide-
lines for the diagnosis and management of atrial fibrillation
developed in collaboration with the European Association for
Cardio-Thoracic Surgery (EACTS): the task force for the diagno-
sis and management of atrial fibrillation of the European Soci-
ety of Cardiology (ESC) developed with the special contribution
of the European Heart Rhythm Association (EHRA) of the ESC.
Eur Heart J 2021;​42:​373-498.
DOI: 10.1056/NEJMe2210187
Copyright © 2022 Massachusetts Medical Society.

Fluid Resuscitation in Acute Pancreatitis

— Going over the WATERFALL
Timothy B. Gardner, M.D.

Acute pancreatitis, responsible for approximately
300,000 hospital admissions in the United States
annually, is characterized by intense inflamma-
tion of the pancreas that leads to severe disease
in approximately one third of affected patients.1
Because no proven pharmacologic therapy for
acute pancreatitis exists, treatment is largely sup-
portive.2 Intravenous fluid resuscitation is recom-
mended as a fundamental component of initial
supportive therapy in acute pancreatitis, owing
largely to observations that untreated pancreatic
hypoperfusion contributes to poor outcomes
such as pancreatic necrosis and death.3
For the past three decades, multiple studies
— but few randomized, controlled trials — have
investigated the effects of crystalloid fluid type,
rate of infusion, or infused total volume on im-
portant clinical outcomes in patients with acute
pancreatitis. Although lactated Ringer’s solution
is firmly established as the crystalloid of choice
because of its antiinflammatory properties, con-
troversy exists regarding the rate and volume of
fluid resuscitation.4 Most major society guide-
lines recommend aggressive early fluid resusci-
tation on the basis of data showing the clinical
determinant of underresuscitation, but there is
contradictory evidence from randomized, con-
trolled trials arguing that overaggressive early
resuscitation leads to poor clinical outcomes,
including greater rates of sepsis and death.5-7 In
essence, a well-designed, prospective trial to an-
swer the question “How much lactated Ringer’s
solution is too much?” needed to be performed.
In this issue of the Journal, de-Madaria and
colleagues8 present the results of a landmark
multicenter, randomized trial — WATERFALL
(the Early Weight-Based Aggressive vs. Nonag-
gressive Goal-Directed Fluid Resuscitation in the
Early Phase of Acute Pancreatitis: an Open-Label
Multicenter Randomized Controlled Trial) —
which definitively provides the answer. The trial
is so clinically relevant because of its choice of
real world–appropriate aggressive-resuscitation
and moderate-resuscitation treatment groups, its
use of pancreatitis severity as the main clinical
outcome, and its reliance on the carefully de-
fined variable of fluid overload as the main
safety outcome. Unlike in most other random-
ized, controlled trials of fluid resuscitation in
acute pancreatitis, patients with varying baseline
pancreatitis severity were included, and changes
in the rate of resuscitation were determined on
the basis of a dynamic assessment of hemody-
namic testing, imaging, and clinical factors.

1038 n engl j med 387;11 nejm.org September 15, 2022

The New England Journal of Medicine

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Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Editorials
Although statistical significance was not ob-
served with regard to any of the clinically impor-
tant outcomes, the results generally favored the
moderate-resuscitation group. The data and safe-
ty monitoring board terminated the trial at the
first interim safety analysis on the basis of the
development of fluid overload in 20.5% of the
patients in the aggressive-resuscitation group, as
compared with 6.3% of those in the moderate-
resuscitation group. The smaller-than-planned
sample size may have contributed to the lack of
significant findings with respect to the primary
outcome. In addition, the total volume of fluid
given over the 72-hour trial period was higher in
the aggressive-resuscitation group than in the
moderate-resuscitation group (8.3 vs. 6.6 liters)
— a finding that indicates that not only should
the rate of resuscitation be slower but the total
infused volume should be lower. These results
are stunning and, given the carefully crafted
trial methods, irrefutable.
What can we conclude therefore from this
trial? First, clinicians should focus on a steady
rate of initial resuscitation — no more than 1.5 ml
per kilogram of body weight per hour — and
should administer a bolus of 10 ml per kilogram
only if there are signs of initial hypovolemia.
Second, careful clinical and hemodynamic mon-
itoring are essential during the first 72 hours
after admission to make sure that patients re-
main euvolemic and to avoid fluid overload.
Third, diuresis in patients with fluid overload in
the first 72 hours is most likely beneficial and
certainly not detrimental to important clinical
outcomes.
Finally, a main conclusion of this trial is that
medical pancreatologists as a specialty now need
to focus on trials evaluating other pharmaco-
logic therapies instead of crystalloid fluids. Al-
though this trial showed a greater clinical benefit
in the moderate-resuscitation group, the inci-
n engl j med 387;11
The New England Journal of Medicine
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Copyright © 2022 Massachusetts Medical Society. All rights reserved.
dence of moderately severe or severe pancreatitis
was still 17.3%, the incidence of local complica-
tions was 16.5%, and organ failure occurred in
3.9% of the patients in that group. Performing
randomized, controlled trials in acute pancreati-
tis is notoriously difficult, and the limited hu-
man and financial resources that are available
for appropriately powered trials in this field post-
WATERFALL are much better spent on compar-
ative-effectiveness and placebo-controlled trials
evaluating new therapeutic agents. Now that we
have gone over the WATERFALL, it is time to
look downstream at new targets to treat this
challenging disease.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Section of Gastroenterology and Hepatology, Dart-
mouth–Hitchcock Medical Center, Lebanon, NH.
1. Peery AF, Crockett SD, Murphy CC, et al. Burden and cost of
gastrointestinal, liver, and pancreatic diseases in the United
States: update 2018. Gastroenterology 2019;​156(1):​254-272.e11.
2. Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN.
Initial medical treatment of acute pancreatitis: American Gas-
troenterological Association Institute technical review. Gastro-
enterology 2018;​154:​1103-39.
3. Gardner TB, Vege SS, Pearson RK, Chari ST. Fluid resuscita-
tion in acute pancreatitis. Clin Gastroenterol Hepatol 2008;​6:​
1070-6.
4. Zhou S, Buitrago C, Foong A, et al. Comprehensive meta-
analysis of randomized controlled trials of lactated Ringer’s
versus normal saline for acute pancreatitis. Pancreatology 2021;​
21:​1405-10.
5. Crockett SD, Wani S, Gardner TB, Falck-Ytter Y, Barkun AN.
American Gastroenterological Association Institute guideline
on initial management of acute pancreatitis. Gastroenterology
2018;​154:​1096-101.
6. Mao E-Q, Fei J, Peng Y-B, Huang J, Tang Y-Q, Zhang S-D.
Rapid hemodilution is associated with increased sepsis and
mortality among patients with severe acute pancreatitis. Chin
Med J (Engl) 2010;​123:​1639-44.
7. Banks PA, Bollen TL, Dervenis C, et al. Classification of
acute pancreatitis — 2012: revision of the Atlanta classification
and definitions by international consensus. Gut 2013;​62:​102-11.
8. de-Madaria E, Buxbaum JL, Maisonneuve P, et al. Aggressive
or moderate fluid resuscitation in acute pancreatitis. N Engl J
Med 2022;​387:989-1000.
DOI: 10.1056/NEJMe2209132
Copyright © 2022 Massachusetts Medical Society.
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